Cyclic ketones, their preparation and their use in the synthesis of amino acids

ABSTRACT

A method is provided for making an enantiomerically pure compound of the formula:  
                 
 
in which R and R′ represent C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 3 -C 10  cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents in compound (II) being trans. Conjugate addition is carried out between an organometallic nucleophile that provides a group R as defined above and (R)-4-acetoxycyclopent-2-en-1-one, (S)-4-acetoxycyclopent-2-en-1-one or a similar compound in which acetoxy is replaced by another leaving group to give, e.g. in the case of the acetoxy compound, a trans 3,4-disubstituted addition product of formula III or IV;

FIELD OF THE INVENTION

The present invention relates to methods for the synthesis of alkyl- andalkenyl- and cycloalkyl-substituted cyclopentanones that are usefulinter alia as intermediates for the synthesis of analogues of gabapentin(Neurontin®). It also relates to methods for the synthesis of gabapentinanalogues using these intermediates, and also to certain novelintermediates per se.

BACKGROUND TO THE INVENTION

Gabapentin (Neurontin®) is an anti-convulsant agent that is useful inthe treatment of epilepsy and that has recently been shown to be apotential treatment for neurogenic pain. It is1-(aminomethyl)-cyclohexaneacetic acid of structural formula:

Gabapentin is one of a series of compounds of formula

in which R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or 6.These compounds are described U.S. Pat. No. 4,024,175 and its divisionalU.S. Pat. No. 4,087,544. Their disclosed uses are: protective effectagainst cramp induced by thiosemicarbazide; protective action againstcardiazole cramp; the cerebral diseases, epilepsy, faintness attacks,hypokinesia, and cranial traumas; and improvement in cerebral functions.The compounds are useful in geriatric patients. The disclosures of theabove two patents are hereby incorporated by reference.

WO 99/21824, whose disclosure is also incorporated by reference,discloses further cyclic amino acids that are useful in the treatment ofepilepsy, faintness attacks, neurodegenerative disorders, depression,anxiety, panic, pain, neuropathological disorders, gastrointestinaldisorders such as irritable bowel syndrome (IBS) and inflammation,especially arthritis. The compounds disclosed include those of theformula:

and salts thereof, in which:

R is hydrogen or a lower alkyl;

R¹ to R⁸ are each independently selected from hydrogen, straight orbranched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine,chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl,trifluoromethyl, —CO₂H, —CO₂R¹⁵, —CH₂CO₂H, —CH₂CO₂R¹⁵, —OR¹⁵ wherein R¹⁵is a straight or branched alkyl of from 1 to 6 carbons, phenyl, orbenzyl, and R¹ to R⁸ are not simultaneously hydrogen.

The compounds of WO 99/21824 may be synthesized:

-   using a general strategy (General Scheme 1) outlined by G. Griffiths    et al., Helv. Chim. Acta, 1991; 74:309;-   analogously to the published procedure for the synthesis of    3-oxo-2,8-diazaspiro[4,5]decane-8carboxylic acid tert-butyl ester,    see P. W. Smith et al., J. Med. Chem., 1995; 38:3772 (General Scheme    2);-   by the methods outlined by G. Satzinger et al., (Ger Offen    2,460,891; U.S. Pat. No. 4,024,175, and Ger Offen 2,611,690; U.S.    Pat. No. 4,152,326) (General Schemes 3 and 4);-   by a route outlined by G. Griffiths et al., Helv. Chim. Acta, 1991;    74:309 (General Scheme 5).

Intermediates disclosed in WO 99/21824 include the following:

Our U.S. Patent Application 60/169,602, the disclosure of which is alsoincorporated herein by reference, describes and claims methods for thestereocontrolled synthesis of five-member ring Gabapentin analogues thatare pure stereoisomers of compounds of formulae shown below and to saltsthereof.

wherein R represents C₁-C₁₀ alkyl and C₃-C₁₀ cycloalkyl. The synthesisstarts with the Knoevenagel condensation of a 3-substitutedcyclopentanone of the kind described above with ethyl cyanoacetate andproceeds via the key intermediates

A method for preparing a compound of formula (1) in the followingreaction scheme and pharmaceutically acceptable salts thereof comprises:

-   a) adding ethyl cyanoacetate to a mixture of a chiral cyclopentanone    of formula (1) in a solvent to which a C₁-C₆ carboxylic acid and an    amphoteric catalyst were added, and stirring the mixture to produce    the alkene of formula (2);-   b) adding the product of Step a) above to a mixture of    benzylmagnesium chloride in a dry solvent to produce the addition    product of formula (3);-   c) adding the product of Step b) above to a mixture of a base in a    solvent and stirring the mixture to produce the carboxylic acid of    formula (4);-   d) contacting the product of Step c) above with    (S)-α-methyl-benzylamine in a solvent, and recrystallizing the salt    so formed to produce the enriched diastereomer of formula (5) as the    (S)-α-methyl-benzylamine salt;-   e) adding the product of Step d) to an inorganic acid dissolved in a    solvent and stirring to produce the carboxylic acid of formula (6);-   f) adding the product of Step e) to a mixture of iodomethane in a    solvent to which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added,    and stirring to produce the ester of formula (7);-   g) adding the product of Step f) to a mixture of carbon    tetrachloride and acetonitrile to which water, sodium periodate, and    ruthenium(III) chloride were added, and stirring to produce the    carboxylic acid of formula (8);-   h) adding the product of Step g) to a mixture of an amine base and a    solvent to which diphenylphosphoryl azide (DPPA) was added, and    stirring to produce the isocyanate of formula (9);-   i) adding the product of Step h) to a solvent to which methanol was    added, and stirring to produce the carbamate of formula (10);-   j) adding the product of Step i) to a solvent to which aqueous    hydrochloric acid was added, and stirring to produce a compound of    Formula Ia;-   k) converting the product of Step j) to a compound of Formula I, and    further converting, if desired, to a pharmaceutically acceptable    salt by known means:

Preparation of a compound of formula II can proceed by a method whichinvolves following the above-described sequence of steps (a) to (e) toproduce the intermediate of step (6), and thereafter following thefurther steps indicated below:

-   f) adding the product of Step e) to a mixture of an amine base and a    solvent to which diphenylphosphoryl azide (DPPA) was added, and    stirring to produce the isocyanate of formula (11);-   g) adding the product of Step f) to a solvent to which methanol was    added and stirring to produce the carbamate of formula (12);-   h) adding the product of Step g) to a mixture of carbon    tetrachloride and acetonitrile to which water, sodium periodate, and    ruthenium(III) chloride were added, and stirring to produce the    carboxylic acid of formula (13);-   i) adding the product of Step h) to a solvent to which aqueous    hydrochloric acid was added, and stirring to produce a compound of    Formula IIa;-   k) converting the product of Step i) to a compound of Formula I, and    further converting, if desired, to a pharmaceutically acceptable    salt by known means:

An alternative route to the compounds of formula (II), also proceedingfrom compound (6) above involves the further steps of:

-   f) adding oxalyl chloride to a mixture of the product of Step e) and    a solvent to which N,N-dimethylformamide (DMAF) was added, and    stirring to produce the acid chloride of formula (14);-   g) adding the product of Step f) to a mixture of tert-butyl alcohol    in a solvent to which an amine base was added, and stirring to    produce the ester of formula (15);-   h) adding the product of Step g) to a mixture of carbon    tetrachloride and acetonitrile to which water, sodium periodate, and    ruthenium(III) chloride were added, and stirring to produce the    carboxylic acid of formula (16);-   i) adding the product of Step h) to a solvent to which methanol and    (trimethylsilyl)diazomethane were added, and stirring to produce the    bis ester of formula (17);-   j) adding an acid to a mixture of the product from Step i) and a    solvent and stirring to produce the carboxylic acid of formula (18);-   k) adding the product of Step j) to a mixture of an amine base and a    solvent to which diphenylphosphoryl azide (DPPA) was added, and    stirring to produce the isocyanate of formula (19);-   l) adding the product of Step k) to a solvent to which methanol was    added and stirring to produce the carbamate of formula (20);-   m) adding the product of Step 1) to a solvent to which aqueous    hydrochloric acid was added, and stirring to produce a compound of    Formula IIa;-   n) converting the product of Step m) to a compound of Formula II,    and further converting, if desired, to a pharmaceutically acceptable    salt by known means:

Compounds of formula (III) can be prepared by processes that involve thesame steps as those for the compounds of formula (I), for example byfollowing the sequence of reactions set out below:

Similarly, compounds of formula (IV) may be made by a sequence ofreactions analogous to those described above:

It will be noted that the synthetic methods disclosed in both WO99/21824 and USSN 60/169602 rely on 3- or 3,4-substitutedcyclopentanones.

SUMMARY OF THE INVENTION

This invention is concerned with the problem that the cyclopentanonesavailable up to now have been limited in their range of stereoisomersand substituents because they have been derived from natural sources, orhave been complex. For example, (R)-3-methyl-cyclopentanone is acompound that is readily available commercially from natural sources,whereas (S)-3-methyl-cyclopentanone is not. It is an object of theinvention to provide a simple stereospecific synthetic route to3-substituted or 3,4-disubstituted cyclopentanones that permits a rangeof desired substituents to be introduced and a range of desiredstereoisomers to be made.

That problem is solved, according to the invention, by a process methodof making an enantiomerically pure compound of the formula (I) or (II):

wherein R and R′ represent C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₃-C₁₀cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, thesubstituents in compound (II) being trans, which method comprises:

-   -   conjugate addition of an organometallic nucleophile that        provides a group R as defined above to a compound of the        formula (III) or (IV):        wherein X represents a leaving group (e.g. an acetoxy group as        in (R)-4-acetoxycyclopent-2-en-1-one or        (S)-4-acetoxycyclopent-2-en-1-one) to give a trans        3,4-disubstituted addition product of formula (V) or (VI) in        which R and X are as previously defined;        eliminating the leaving-group from the addition product of        formula (V) or (VI) to give an (R)- or (S)-4-alkyl or 4-alkenyl        cyclopent-2-en-1-one of formula (VII) or (VIII)        and either

(i) hydrogenation of the compound of formula (VII) or (VII) to give acyclopentanone of formula (I) or

(ii) conjugate addition of a second organometallic nucleophile thatprovides a group R′ as defined above to the compound of formula (VII) or(VIII) to give a trans 3,4-disubstituted addition product of formula(II).

While conjugate addition to conjugated cyclopentenones is known for softnucleophiles such as enolates, sulfides and bromides, such reactionshave not been carried out with carbon-based nucleophiles with a view toproducing chirally pure ketones. The group AcO— in the starting materialbrings about stereospecific addition of the group R during the firstMichael addition, and where a second Michael addition is carried out,the group R that is already present in the compound of formula (VII) or(VIII) brings about stereospecific addition of the group R′. Theenantiomeric purity of the resulting compounds of formula (I) and (II)can be tested by reacting them with an asymmetric diol such as(2R,3R)-2,3-butanediol to give an acetal having an additional asymmetriccentre in the molecule, e.g

and obtaining the NMR spectrum of the resulting chiral acetal. If thestarting material is an enantiomeric mixture, then the two resultingcyclic acetals will be diastereomeric and give distinguishable peaks inthe NMR spectrum provided that the enantiomeric impurity is present inan amount of 2% or above. No such peaks have been observed in thematerials that we have made, and we therefore believe that the method ofthe invention gives desired enantiomers with a purity of at least 98%.

According to a furrer aspect of the invention, a compound of formula (I)and (II) may be converted in manner known per se to a gabapentinanalogue of one of the formulae shown below:

in which the substituents R and R′ and the wedges have the meaningsindicated above, and may be further converted into a pharmaceuticallyacceptable salt thereof.

Conversion to a compound of formula (XI)-(XIV) may, for example, followone of the general schemes disclosed in WO 99/21824, or it may followthe Knoevenagel addition route disclosed in USSN 60/169602. In thelatter case, there may be produced the key intermediates (XV)-(XVIII)shown below:

in which the substituents R and R′ and the wedges have the meaningsindicated above. Thereafter, the intermediate of formula (XV)-(XVIII)may be converted to a compound of formula (I) or (II) by one of thethree principal strategies disclosed in USSN 60/169602, i.e. (i)transforming the phenyl ring to a carboxylic acid and then to an amine;(ii) transforming the carboxylic acid group into an amine and oxidizingthe phenyl group to an acid, or (iii) protecting the carboxylic acidgroup, oxidizing the phenyl ring to a second carboxylic acid group,protecting the second carboxylic acid group, selectively de-protectingthe first carboxylic acid group, transforming the first carboxylic acidgroup to an amine, and de-protecting the second carboxylic acid group.

Certain of the present intermediates are believed to be new. In afurther aspect, therefore, the invention provides enantiomerically purecompounds of the formula:

wherein R and R′ represent C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₃-C₁₀cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, thesubstituents being trans, and at least one of R and R′ not being methyl.

DESCRIPTION OF PREFERRED FEATURES

As previously stated, the compounds of the invention can be prepared inchirally pure form from (R)-4-acetoxycyclopent-2-en-1-one (1) or(S)-4-acetoxycyclopent-2-en-1-one (2).

The reactions of 4-Oxo-2-cyclopentenyl Acetate(4-Acetoxy-2-cyclopenten-1-one) have been reviewed by M. Harre, P.Raddatz, R. Walenta and E. Winterfeldt, Angew. Chem. Int. Ed. Engl.,1982, 21, 480. It has been synthesised in enantiomerically pure formusing two main approaches:

-   Acetylation of chirally pure 4-hydroxy-2-cyclopenten-1-one, see K.    Ogura, M. Yamashita and G. Tsuchihashi, Tetrahedron Letters,    1976, 759. For examples of approaches to chiral    4-hydroxy-2-cyclopenten-1-one see the following and references    therein: S. R. Ghorpade, K. B. Bastawade, D. V. Gokhale, P. D.    Shinde, V. A. Mahajan, U. R. Kalkote and T. Ravindranathan,    Tetrahedron Asymmetry, 1999, 10, 4115; S. P. Khanapure, N.    Najafi, S. Manna, J-J. Yang and J. Rokach, J. Org. Chem., 1995, 60,    7548; E. Mezzina, D. Savoia, E. Tagliavini, C. Trombini and A.    Umani-Ronchi, J. Chem. Soc. Perkin Trans. 1, 1989, 845; M.    Kitamura, K. Manabe and R. Noyori, Tetrahedron Letters, 1987, 28,    4719; R. Noyori, I. Tomino, M. Yamada and M. Nishizawa, J. Am. Chem.    Soc., 1984, 106, 6717; M. Suzuki, T. Kawagishi, T. Suzuki and R.    Noyori, Tetrahedron letters, 1982, 23, 4057; R. Noyori, Pure & Appl.    Chem., 1981, 53, 2315; T. J. N. Watson, T. T. Curran, D. A.    Hay, R. S. Shah, D. L. Wenstrup and M. E. Webster, Organic Process    Research & Development, 1998, 2, 357; S. R. Ghorpade, K. B.    Bastawade, D. V. Gokhale, P. D. Shinde, V. A. Mahajan, U. R. Kalkote    and T. Ravindranathan, Tetrahedron: Asymmetry, 1999, 10, 4115-4122).-   Oxidation of 3-acetoxy-5-hydroxycyclopent-1-enes, for example    see: M. Korach, D. R. Nielsen and W. H. Rideout, Org. Synth,    Collect. Vol. 5, 1973, 414; D. R. Deardoff and D. C. Myles, Org.    Synth., 1989, 67, 114; D. R. Deardorff, C. Q. Windham and C. L.    Craney, Org. Synth., 1995, 73, 25; C. R. Johnson and S. J. Bis,    Tetrahedron Letters, 1992, 33, 7287.

The following reactions may be used to make compounds according to theinvention:

-   A) Conjugate addition to a cyclopent-2-en-1-one (1) or (2) can be    carried out using an organo-Grignard reagent in the presence of    dimethylzinc giving a trans 3,4-disubstituted intermediate e.g. an    addition product of formula (3) or (4). In particular, the chiral    cyclopentenone of formula (1) or (2) may be added to the    organo-Grignard reagent or to an organo-lithium reagent in the    presence of a dialkylzinc or zinc chloride or a copper (I) salt or a    trialkylaluminium in a solvent, for example, tetrahydrofuran,    1,4-dioxane, n-heptane, toluene, diethyl ether or tert-butyl methyl    ether at a temperature from −100° C. to 0° C. to produce said    addition product.-   B) Adding the product of step A) above to a mixture of base, for    example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBBU),    1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethyl    guanidine (TMG), lithium hydride or sodium hydride in a solvent, for    example, dichloromethane, diethyl ether, tetrahydrofliran,    tert-butyl methyl ether or 1,4-dioxane to produce an elimination    product of formula (5) or (6).-   C) Adding the product of step B) above to a mixture of    organo-Grignard reagent or organo-lithium reagent in the presence of    a dialkylzinc or zinc chloride or a copper (I) salt or a    trialkylaluminium salt in a solvent, for example, tetrahydroflran,    1,4-dioxane, n-heptane, toluene, diethyl ether or tert-butyl methyl    ether at a temperature from −100° C. to 0° C. can be used to produce    an addition product of formula (7) or (8).-   D) Adding the product of step B) above to a hydrogenation catalyst,    for example, palladium on charcoal, platinum oxide, Raney nickel,    Rhodium on alumina in a solvent, for example, ethyl acetate or    methanol under a hydrogen atmosphere at 1 to 30 atmospheres pressure    and at a temperature in the range 0-60° C., can be used to make a    product of formula (9) or (10).

The above described reactions are illustrated in the following schemes:

An example of the utility of the above reaction scheme is shown below:

Compounds that can be made by the present process are shown below, andthe following are believed to be new:

-   -   (3S,4S)-3,4-diethyl-cyclopentanone;    -   (3R,4R)-3,4-diethyl-cyclopentanone;    -   (3S,4S)-3-ethyl-4-methyl-cyclopentanone;    -   (3R,4R)-3-ethyl-4-methyl-cyclopentanone;    -   (3S,4S)-3-methyl-4-propyl-cyclopentanone;    -   (3R,4R)-3-methyl-4-propyl-cyclopentanone;    -   (3S,4S)-3-ethyl-4-propyl-cyclopentanone; and    -   (3R,4R)-3-ethyl-4-propyl-cyclopentanone.

Other leaving groups may be present in the starting materials employedin the above process in place of the acetoxy compounds, and in generalany compound that is available in optically pure form and that has a4-substituent that permits stereospecific addition to the en-oneconjugated system and can then undergo elimination can be used. Examplesof such leaving groups are halides and sulfonic acid ester groups.Examples of alternative starting materials include:

For preparation see T. Hirao, S. Mikami, M. Mori, Y. Ohshiro, Tet.lett., 1991, 32(14), 1741-4. For stereospecific preparation of R and Senantiomers see R. Gerdil, H. Liu, G. Bernardinelli, Helv. Chim. Acta.,1999, 82(3), 418-34.

For preparation see: F. Gavina, A. Costero, A. Gonzalez, S. Luis, J.Org. Chem., 1987, 52(14), 2997-9; C. H. DePuy, M. Isaks, K. L. Eilers,G. F. Morris, J. Org. Chem., 1964, 29, 3503-10; J. A. Bloodworth, H. J.Eggelte, J. Chem. Soc. Perkin Trans. 1, 1981, 12, 3272-8.

For preparation of the above two compounds or the class of compounds ofthe third formula, in which R=straight or branched alkyl of C₁-C₆, seeM. Minamii, Y. Ueda, JP 62116537 (JP 85-262204), JP 85-167970 and M.Minamii, Y. Ueda, EP-A-0170506.

The invention will now be further described in the following Examples.

EXAMPLE 1 Enantiomerically Pure (S)-3-n-propyl-cyclopentanone (3)

(3R,4R)-3-acetoxy-4-n-propyl-cyclopentanone (1)

n-Propylmagnesium chloride (15.7 ml of a 2M solution in ether, 31.4mmol) was added slowly to a stirred solution of dimethylzinc (15.7 ml ofa 2M solution in toluene, 31.4 mmol) in THF (80 ml) under argon at 0° C.After 30 minutes, the mixture was cooled to −78° C. and(R)-4-acetoxycyclopent-2-enone (4.0 g, 28.5 mmol) in THF (45 ml) wasadded dropwise over 1 hour. The reaction mixture was stirred for afurther 20 minutes and then quenched by the addition of saturatedammonium chloride solution (20 ml). The reaction mixture was allowed towarm to room temperature, diluted with 1N hydrochloric acid (100 ml) andextracted with ether (3×200 ml). The organic layer was washed with brine(200 ml), dried (MgSO₄) and the solvent was removed under reducedpressure to yield the acetoxy cyclopentanone 1 as a solution in toluenewhich was used without further purification in the next step.υ_(max)(film)/cm⁻¹ 1740 (C═O).

δ_(H)(400 MHz; CDCl₃) 5.08 (1H, m, CHOAc), 2.70 (1H, dd, J 19.2, 5.9),2.59 (1H, dd, J 8.1, 1.2), 2.34 (1H, m), 2.23 (1H, dd, J 19.1, 4.6),2.07 (3H, s, OCOMe), 1.98 (1H, dd, J 18.4, 6.4), 1.54 (1H, m), 1.46-1.21(3H, m), 0.94 (3H, t, J 7.1, Me).

(R)-4-n-propyl-cyclopent-2-enone (2)

The acetoxy cyclopentanone 1 (approx. 28.5 mmol) in ether (40 ml) wasadded dropwise over 1 hr to a stirred solution of DBU (4.27 ml, 28.5mmol) in ether (50 ml) at −40° C. under argon. The mixture was allowedto warm to −30° C. and stirred for 30 minutes before being quenched withdilute hydrochloric acid (20 ml). The reaction mixture was partitionedbetween ether (100 ml) and 1N HCl (150 ml). The organic layer wasseparated and the aqueous layer was further extracted with ether (2×100ml). The combined ether layers were washed with brine, dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waschromatographed (SiO₂, pentane-ether, 1:0 to 8:2) to give thepropylcyclopentenone 2 (2.4 g, 68% from (R)-4-acetoxycyclopent-2-enone).υ_(max)(film)/cm⁻¹ 1708 (C═O).

δ_(H)(400 MHz; CDCl₃) 7.64 (1H, dd, J 5.6, 2.4, CH═CHC═O), 6.14 (1H, dd,J 5.6, 2.0, CH═CHC═O), 2.75 (1H, m), 2.53 (1H, dd, J 18.8, 6.4,CH_(A)H_(B)C═O), 2.00 (1H, dd, J 18.8, 2.0, CH_(A)H_(B)C═O) 1.60-1.20(4H, m), 0.96 (3H, t, J 6.8, Me).

(S)-3-n-propylcyclopentanone (3)

A mixture of 2 (1.2 g, 9.7 mmol) and 10% palladium on charcoal(catalytic quantity) in ethyl acetate (30 ml) was shaken in hydrogen at55 psi and at 30° C. for 6 hours. The reaction mixture was filtered andthe solvent was evaporated under reduced pressure. The residue waschromatographed (SiO₂, pentane-ether, 1:0 to 9:1) to give the3-propylcyclopentanone 3 (1.07 g, 88%).υ_(max)(film)/cm⁻¹ 1744 (C═O).

δ_(H)(400 MHz; CDCl₃) 2.29 (1H, dd, J 16.0, 8.4), 2.38 (1H, dd, J 18.8,7.6), 2.21-2.09 (2H, m), 1.79 (1H, dd, J 18.0, 9.6), 1.56-1.34 (6H, m),0.93 (3H, t, J 7.2, Me).

Enantiomeric Purity By Conversion To Acetal (7)

The ketone 3 (0.12 g, 0.95 mmol), (2R,3R)-(-)-2,3-butanediol (0.087 ml,0.96 mmol) and p-toluenesulphonic acid (0.018 g, 0.095 mmol) wererefluxed together in benzene (10 ml) for 3 hours using a Dean-Starktrap. The reaction mixture was allowed to cool, taken up in ethylacetate (100 ml) and washed with saturated sodium bicarbonate solution,brine, dried (MgSO₄) and concentrated in vacuo to give a singlediastereoisomeric acetal 7 (0.12 g, 65%).

δ_(H)(400 MHz; CDCl₃) 3.61-3.57 (2H, m), 2.1-1.76 (5H, m), 1.47-1.40(2H, m), 1.35-1.20 (10H, m), 0.88 (3H, t, J 6.8, Me); δ_(C)(CDCl₃)117.2, 78.3, 78.1, 44.6, 38.4, 37.6, 37.2, 30.1, 21.3, 17.2, 17.1, 14.2.

EXAMPLE 2 (3R,4R)-3-methyl-4-n-propyl-cyclopentanone (4)

Methylmagnesium chloride (7.1 ml of a 3M solution in ether, 21.3 mmol)was added slowly to a stirred solution of dimethylzinc (5.3 ml of a 2Msolution in toluene, 10.6 mmol) in TBF (80 ml) under argon at 0° C.After 30 minutes the mixture was cooled to −78° C. and 2 (1.2 g, 9.7mmol) in THF (45 ml) was added dropwise over 1 hour. The reactionmixture was stirred for 20 minutes and then quenched by the addition ofsaturated amnmonium chloride solution (20 ml). The reaction mixture wasallowed to warm to room temperature, diluted with 1N hydrochloric acid(100 ml) and extracted with ether (3×200 ml). The organic layer waswashed with brine (200 ml), dried (MgSO₄) and the solvent was removedunder reduced pressure to yield 4 as a solution in toluene which waspurified by column chromatography (SiO₂, pentane-ether, 1:0 to 9:1 togive the cyclopentanone 4 (0.86 g, 63%).υ_(max)(CDCl₃)/cm⁻¹ 1733 (C═O).

δ_(H)(400 MHz; CDCl₃) 2.49-2.42 (2H, m), 1.87-1.80 (3H, m), 1.79-1.61(2H, m), 1.80-1.43 (3H, m), 1.12 (3H, d, J 6.1, Me), 0.93 (3H, t, J 7.3,Me); δ_(C)(CDCl₃) 220.0, 48.1, 46.2, 45.5, 38.4, 37.0, 232.1, 19.6,15.8.

Enantiomeric Purity By Conversion To Acetal 8

The ketone 4 (0.12 g, 0.86 mmol), (2R,3R)-(-)-2,3-butanediol (0.086 ml,0.94 mmol) and p-toluenesulphonic acid (0.0163 g, 0.086 mmol) wererefluxed together in benzene (10 ml) for 3 hours using a Dean-Starktrap. The reaction mixture was allowed to cool, taken up in ethylacetate (100 ml), washed with saturated sodium bicarbonate solution,brine, dried (MgSO₄) and concentrated in vacuo to give 8 (0.08 g, 44%).

δ_(H)(400 MHz; CDCl₃) 3.61-3.58 (2H, m), 2.51-2.39, 2.27, 2.19-2.06,1.90-1.60 (6H, m), 1.60-1.04 (10H, m), 0.98 (3H, d, J 6.6, Me), 0.89(3H, t, J 7.3, Me); δ_(C)(400 MHz; CDCl₃) 115.8, 78.2, 78.1, 47.2, 45.1,45.0, 38.4, 36.5, 21.4, 18.8, 17.3 (×2), 14.4.

EXAMPLES 3 & 4 (R)-3-n-propyl-cyclopentanone (5) And(3S,4S)-3-methyl4-n-propyl-cyclopentanone (6)

Ketones 5 and 6 were made using the same procedures as in the precedingexamples, but starting from (S)-4-acetoxycyclopent-2-enone.

Enantiomeric Purity By Conversion To Chiral Acetals 9, 10.

The enantiomeric purity of ketone 5 was confirmed by making acetal 9using the procedure of the foregoing examples.

δ_(H)(400 MHz; CDCl₃) 3.60-3.48 (2H, m), 2.45-1.76 (5H, m), 1.44-1.41(2H, m), 1.38-1.14 (10H, m), 0.88 (3H, t, J 7.1, mE); δ_(C)(CDCl₃)117.2, 78.2, 78.1, 44.9, 38.2, 38.0, 37.7, 30.5, 21.3, 17.0, 16.9, 14.2.

The enantiomeric purity of ketone 6 was confirmed by making acetal 10using the procedure of the above examples.

δ_(H)(400 MHz; CDCl₃) 3.56-3.49 (2H, m), 2.49-2.22, 2.13-2.04, 1.90-1.62(6H, m), 1.60-1.02 (10H, m), 0.97 (3H, d, J 6.1, Me), 0.89 (3H, t, J7.3, Me); δ_(C)(CDCl₃) 115.7, 78.1, 47.6, 45.5, 45.2, 38.6, 36.0, 21.4,18.2, 16.9 (×2), 14.4.

EXAMPLE 5 Enantiomerically Pure (3S,4S)-3,4-dimethylcyclopentanone (13)

The Acetoxy Cyclopentanone 11

Methylmagnesium chloride (11.3 ml of a 3M solution in THF, 33.9 mmol)was added slowly to a stirred solution of dimethylzinc (17.0 ml of a 2Msolution in toluene, 34.0 mmol) in THF (80 ml) at 0° C. under argon.After 20 minutes, the mixture was cooled to −78° C. and(S)-4-acetoxycyclopent-2-enone (4.33 g, 30.9 mmol) in THF (45 ml) wasadded dropwise over 1 hour. The reaction mixture was stirred for afurther 20 minutes and then quenched by the addition of saturatedammonium chloride solution (20 ml). The reaction mixture was allowed towarm to room temperature, diluted with 1N hydrochloric acid (100 ml) andextracted with ether (3×200 ml). The organic layer was washed with brine(200 ml), dried (MgSO₄) and the solvent was removed under reducedpressure to yield the acetoxy cyclopentanone 11 as a solution in toluenewhich was used without further purification in the next step.υ_(max)(film)/cm⁻¹ 1737 (C═O).

δ_(H)(400 MHz; CDCl₃) 5.01 (1H, m, CHOAc), 2.72 (1H, dd, J 19.0, 6.6),2.59 (1H, m), 2.46 (1H, m), 2.24 (1H, dd, J 19.0, 4.6), 2.07 (3H, s,OCOMe), 1.95 (1H, dd, J 18.6, 5.7), 1.13 (3H, d, J 7.1, CHMe).

The Methylcyclopentanone 12

Acetoxy cyclopentanone 11 (approx. 30.9 mmol) in dichloromethane (40 ml)was added dropwise over 1 hour to a stirring solution of DBU (4.6 ml,30.9 mmol) in dichloromethane (50 ml) at −40° C. under argon. Themixture was allowed to warm to −30° C. and stirred for 30 minutes beforebeing quenched with dilute hydrochloric acid (20 ml). The reactionmixture was partitioned between ether (100 ml) and 1N HCl (150 ml). Theorganic layer was separated and the aqueous layer was further extractedwith ether (2×100 ml). The combined ether layers were washed with brine,dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was chromatographed (SiO₂, pentane-ether, 7:3) to givemethylcyclopentenone 12 (1.51 g, 51% from(S)-4-acetoxycyclopent-2-enone).υ_(max)(film)/cm⁻¹ 1715 (C═O).

δ_(H)(400 MHz; CDCl₃) 7.59 (1H, dd, J 5.6, 2.4, CH═CHC═O), 6.14 (1H, dd,J 5.6, 2.0, CH═CHC═O), 3.02 (1H, m), 2.60 (1H, dd, J 18.8, 6.3,CH_(A)H_(B)C═O), 1.95 (1H, dd, J 18.8, 2.2, CH_(A)H_(B)C═O) 1.21 (3H, d,J 7.1, CHMe).

The Dimethylcyclopentanone 13

Methylmagnesium chloride (5.2 ml of a 3M solution in ether, 15.6 mmol)was added slowly to a stirred solution of dimethylzinc (3.9 ml of a 2Msolution in toluene, 7.8 mmol) in THF (20 ml) under argon at 0° C. After30 minutes the mixture was cooled to −78° C. and 12 (0.67 g, 7.0 mmol)in THF (10 ml) was added dropwise over 1 hour. The reaction mixture wasstirred for 20 minutes and then quenched by the addition of saturatedammonium chloride solution (10 ml). The reaction mixture was allowed towarm to room temperature, diluted with 1N hydrochloric acid (40 ml) andextracted with ether (3×50 ml). The organic layer was washed with brine(50 ml), dried (MgSO₄) and the solvent was removed under reducedpressure to yield 13 as a solution in toluene which was purified bycolumn chromatography (SiO₂, pentane-ether, 95:5) to give thedimethylcyclopentanone 13 (0.45 g, 52%).

ti υ_(max)(filmn)/cm⁻¹ 1732 (C═O).

δ_(H)(400 MHz; CDCl₃) 2.50-2.39 (2H, m), 1.89-1.72 (4H, m), 1.12 (6H, d,J 5.6, 2×Me).

Enantiomeric Purity of 13 Was Established By Conversion To Acetal 14

The ketone 13 (0.25 g, 2.23 mmol), (2R,3R)-(-)-2,3-butanediol (0.23 ml,2.45 mmol) and p-toluenesulphonic acid (0.042 g, 0.22 mmol) wererefluxed together in benzene (10 ml) for 3 hours using a Dean-Starktrap. The reaction mixture was allowed to cool, taken up in ethylacetate (100 ml), washed with saturated sodium bicarbonate solution,brine, dried (gSO₄) and concentrated in vacuo to give 14 (0.21 g, 51%).

δ_(C)(CDCl₃) 115.5, 78.0, 47.8, 40.1, 17.7, 16.9.

m/z (CI⁺) 185 (M+H, 70%)

The acetal made from racemic (3RS,4RS)-3,4dimethylketone has signals asshown below:

δ_(C)(CDCl₃) 115.6, 115.5, 78.2, 78.1, 47.8, 47.5, 40.2, 40.0, 18.1,17.7, 17.3, 16.9

EXAMPLE 6 Enantiomerically Pure (S)-3-methylcyclopentanone (16)

The Methylcyclopentenone 15

Compound 15 was prepared using the same method as 12.

The Methylcyclopentanone 16

A mixture of 15 (1.17 g, 12.2 mmol) and 10% palladium on charcoal(catalytic quantity) in ethyl acetate (30 ml) was shaken at 55 psiHydrogen at 30° C. for 6 hours. The reaction mixture was filtered andthe solvent was removed under reduced pressure. The residue waschromatographed (SiO₂, pentane-ether, 9:1) to give the3-methylcyclopentanone 16 (1.09 g, 91%).υ_(max)(film)/cm⁻¹ (C═O) 1731.

δ_(H)(400 MHz; CDCl₃) 2.42-2.08 (5H, m), 1.78 (1H, ddd, J 16.8, 9.3,0.7), 1.51 (1H, m), 1.13 (3H, d, J 6.8).

The Acetal 17

The ketone 16 (0.25 g, 2.55 mmol), (2R,3R)-(-)-2,3-butanediol (0.26 ml,2.80 mmol) and p-toluenesulphonic acid (0.05 g, 0.255 mmol) wererefluxed together in benzene (10 ml) for 3 hours using a Dean-Starktrap. The reaction mixture was allowed to cool, taken up in ethylacetate (100 ml), washed with saturated sodium bicarbonate solution,brine, dried (MgSO₄) and concentrated in vacuo to give the acetal 17(0.20 g, 47%).

δ_(H)(400 MHz; CDCl₃) 3.59 (2H, m), 2.08-1.17 (13H, m), 1.01 (3H, d, J6.8, Me); δ_(C)(CDCl₃) 117.4, 78.3, 78.0, 46.4, 38.0, 32.1, 20.6, 17.2,17.1

The acetal of the racemic 3-methylcyclopentanone has signals as shownbelow:

δ_(C)(CDCl₃) 117.4, 78.3, 78.1 (×2), 78.0, 46.7, 46.4, 38.5, 38.0, 32.5,32.1, 20.6, 20.2, 17.2, 17.1, 16.9 (×2).

EXAMPLE 7 Enantiomerically Pure (3S,4S)-3-ethyl-4-methyl-cyclopentanone(20)

The Acetoxy Cyclopentanone 18

Ethylmagnesium chloride (19.6 ml of a 2M solution in THF, 39.2 mmol) wasadded slowly to a stirred solution of dimethylzinc (19.6 ml of a 2Msolution in toluene, 39.2 mmol) in THF (80 ml) at 0° C. under argon.After 20 minutes, the mixture was cooled to −78° C. and(S)-4-acetoxycyclopent-2-enone (5.0 g, 35.7 mmol) in THF (45 ml) wasadded dropwise over 1 hour. The reaction mixture was stirred for afurther 20 minutes and then quenched by the addition of saturatedammonium chloride solution (20 ml). The reaction mixture was allowed towarm to room temperature, diluted with IN hydrochloric acid (100 ml) andextracted with ether (3×200 ml). The organic layer was washed with brine(200 ml), dried (MgSO₄) and the solvent was removed under reducedpressure to yield the acetoxy cyclopentanone 18 as a solution in toluenewhich was used without further purification in the next step.υ_(max)(film)/cm⁻¹ 1741 (C═O).

δ_(H)(400 MHz; CDCl₃) 5.10 (1H, m, CHOAc), 2.70 (1H, dd, J 19.3, 6.7),2.57 (1H, ddd, J 18.5, 8.3, 1.2), 2.32-2.20 (2H, m), 2.07 (3H, s,OCOMe), 2.00 (1H, m), 1.62 (2H, m), 0.98 (3H, t, J 7.2, Me).

The Ethylcyclopentenone 19

Acetoxy cyclopentanone 18 (approx. 35.7 mmol) in dichloromethane (45 ml)was added dropwise over 1 hr to a stirring solution of DBU (5.34 ml,35.7 mmol) in dichloromethane (100 ml) at −40° C. under argon. Themixture was allowed to warm to −30° C. and stirred for 30 minutes beforebeing quenched with dilute hydrochloric acid (30 ml). The reactionmixture was partitioned between ether (100 ml) and 1N HCl (150 ml). Theorganic layer was separated and the aqueous layer was further extractedwith ether (2×100 ml). The combined ether layers were washed with brine,dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was chromatographed (SiO₂, pentane-ether, 8:2) to giveethylcyclopentenone 19 (3.4 g, 86% from (S)-4-acetoxycyclopent-2-enone).υ_(max)(film)/cm⁻¹ 1713 (C═O).

δ_(H)(400 MHz; CDCl₃) 7.65 (1H, dd, J 5.6, 2.4, CH═CHC═O), 6.16 (1H, dd,J 5.6, 2.0, CH═CHC═O), 2.88 (1H, m), 2.54 (1H, dd, J 19.0, 6.3,CH_(A)H_(B)C═O), 2.02 (1H, dd, J 18.8, 2.2, CH_(A)H_(B)C═O) 1.63 (1H,m), 1.47 (1H, m), 0.99 (3H, t, J 7.6, Me).

The Cyclopentanone 20

Methylmagnesium chloride (22.5 ml of a 3M solution in ether, 67.5 mmol)was added slowly to a stirred solution of dimethylzinc (16.9 ml of a 2Msolution in toluene, 33.8 mmol) in THF (100 ml) under argon at 0° C.After 30 minutes the mixture was cooled to −78° C. and 19 (3.37 g, 30.6mmol) in THF (45 ml) was added dropwise over 1 hour. The reactionmixture was stirred for 20 minutes and then quenched by the addition ofsaturated ammonium chloride solution (25 ml). The reaction mixture wasallowed to warm to room temperature, diluted with 1N hydrochloric acid(100 ml) and extracted with ether (3×100 ml). The organic layer waswashed with brine (50 ml), dried (MgSO₄) and the solvent was removedunder reduced pressure to yield 20 as a solution in toluene which waspurified by column chromatography (SiO₂, pentane-ether, 95:5) to givethe cyclopentanone 20 (2.4 g, 62%).υ_(max)(film)/cm⁻¹ 1738 (C═O).

δ_(H)(400 MHz; CDCl₃) 2.50-2.40 (2H, m), 1.92-1.60 (6H, m), 1.12 (3H, d,J 6.1, Me), 0.93 (3H, t, J 6.5, Me).

Conversion To An Acetal

The ketone 20 (0.22 g, 1.74 mmol), (2R,3R)-(-)-2,3-butanediol (0.18 ml,1.91 mmol) and p-toluenesulphonic acid (0.033 g, 0.174 mmol) wererefluxed together in benzene (10 ml) for 3 hours using a Dean-Starktrap. The reaction nixture was allowed to cool, taken up in ethylacetate (100 ml), washed with saturated sodium bicarbonate solution,brine, dried (gSO₄) and concentrated in vacuo to give 24 (0.19 g, 55%).

δ_(C)(CDCl₃) 115.6, 78.1 (×2), 47.6, 47.1, 44.9, 38.2, 26.2, 19.3, 18.2,16.9, 14.2; m/z (CI⁺) 199 (+H, 82%).

EXAMPLE 8 Enantiomerically Pure (R)-3-ethylcyclopentanone (21)

A mixture of 19 (3.4 g, 30.9 mmol) and 10% palladium on charcoal(catalytic quantity) in ethyl acetate (50 ml) was shaken at 55 psi inhydrogen at 30° C. for 6 hours. The reaction mixture was filtered andthe solvent was removed under reduced pressure. The residue waschromatographed (SiO₂, pentane-ether, 9:1) to give the3-ethylcyclopentanone 21 (3.4 g, 98%).υ_(max)(film)/cm⁻¹ 1737 (C═O).

δ_(H)(400 MHz; CDCl₃) 2.38 (1H, dd, J 18.1, 7.3), 2.29 (1H, dd, J 16.1,8.8), 2.21-2.04 (4H, m), 1.79 (1H, ddd, J 18.1, 9.8, 1.1), 1.47 (2H, m),0.95 (3H, t, J 7.6, Me).

Conversion To Acetal 25

The ketone 21 (0.098 g, 0.874 mmol), (2R,3R)-(-)-2,3-butanediol (0.088ml, 0.96 mmol) and p-toluenesulphonic acid (0.017 g, 0.087 mmol) wererefluxed together in benzene (10 ml) for 3 hours using a Dean-Starktrap. The reaction mixture was allowed to cool, taken up in ethylacetate (100 ml), washed with saturated sodium bicarbonate solution,brine, dried (MgSO₄) and concentrated in vacuo to give 25 (0.12 g, 73%).

δ_(C)(CDCl₃) 117.2, 78.2, 78.1, 44.5, 39.8, 38.0, 30.1, 28.6, 17.0,16.9, 12.5; m/z (CI⁺) 185 (M+H, 75%)

EXAMPLES 10 & 11 (3R,4R)-3 ethyl4-methyl-cyclopentanone (22) And(S)-3-ethyl-cyclopentanone (23)

Compounds 22 and 23 were made using the procedure of the previousexamples.

Conversion To Acetals 26, 27

The enantiomeric purity of ketone 22 was confirmed by making acetal 26using the previously described procedure.

δ_(C)(CDCl₃) 115.7, 78.2, 78.1, 47.3, 46.9, 44.6, 38.0, 26.6, 19.3,18.8, 17.3, 17.2, 14.2; m/z (CI⁺) 199 (M+H, 80%)

The enantiomeric purity of ketone 23 was also confirmed by making acetal26 using the previously described procedure.

δ_(C)(CDCl₃) 117.2, 78.3, 78.1, 44.2, 39.3, 37.6, 29.7, 28.8, 17.2,12.5; m/z (CI⁺) 185 (M+H,78%).

1-29. (canceled)
 30. A method of making an enantiomerically purecompound of the formula (I) or (II):

wherein R and R′ represent C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₃ -C₁₀cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, thesubstituents in compound (II) being trans, which method comprises:conjugate addition of an organometallic nucleophile that provides agroup R as defined above to a compound of the formula (III) or (IV):

wherein X represents a leaving group to give a trans 3,4-disubstitutedaddition product of formula (V) or (VI) in which R and X are aspreviously defined;

eliminating the leaving-group X from the addition product of formula (V)or (VI) to give an (R)- or (S)-4-alkyl or 4-alkenyl cyclopent-2-en-1-oneof formula (VII) or (VIII)

and either (i) hydrogenation of the compound of formula (VII) or (VIII)to give a cyclopentanone of formula (I) or (ii) conjugate addition of asecond organometallic nucleophile that provides a group R′ as definedabove to the compound of formula (VII) or (VIII) to give a trans3,4-disubstituted addition product of formula (II).
 31. The method ofclaim 30, when used to make an (S)-compound of formula (I).
 32. Themethod of claim 30, when used to make an (R)-compound of formula (I).33. The method of claim 30, when used to make a (3S,4S)-compound offormula (II).
 34. The method of claim 30, when used to make a(3R,4R)-compound of formula (II).
 35. The method of claim 30, when usedto make a compound in which R and R′ (if present) represent methyl,ethyl or n-propyl.
 36. The method of claim 30, when used to make any ofthe following compounds: (S)-3-methylcyclopentanone;(R)-3-methylcyclopentanone; (S)-3-ethylcyclopentanone;(R)-3-ethylcyclopentanone; (S)-3-n-propylcyclopentanone;(R)-3-n-propylcyclopentanone; (3S,4S)-3,4-dimethyl-cyclopentanone;(3R,4R)-3,4-dimethyl-cyclopentanone; (3S,4S)-3,4-diethyl-cyclopentanone;(3R,4R)-3,4-diethyl-cyclopentanone;(3S,4S)-3-ethyl-4-methyl-cyclopentanone;(3R,4R)-3-ethyl-4-methyl-cyclopentanone;(3S,4S)-3-methyl-4-propyl-cyclopentanone;(3R,4R)-3-methyl-4-propyl-cyclopentanone;(3S,4S)-3-ethyl-4-propyl-cyclopentanone;(3R,4R)-3-ethyl-4-propyl-cyclopentanone.
 37. The method of claim 30,wherein the elimination product of formula (VII) or (VIII) is treatedwith hydrogen at a pressure of 1-30 atmospheres at a temperature in therange 0-60° C. in a solvent and in the presence of a hydrogenationcatalyst to give a compound of formula (I).
 38. The method of claim 30wherein the elimination product of formula (VII) or (VIII) is treatedwith hydrogen at a pressure of 1-30 atmospheres at a temperature in therange 0-60° C. in a solvent and in the presence of a hydrogenationcatalyst to give a compound of formula (I); and wherein thehydrogenation catalyst is selected from palladium on charcoal, platinumoxide, Raney nickel, and rhodium on alumina.
 39. The method of claim 30,wherein the elimination product of formula (VII) or (VIII) is treatedwith hydrogen at a pressure of 1-30 atmospheres at a temperature in therange 0-60° C. in a solvent and in the presence of a hydrogenationcatalyst to give a compound of formula (I); and wherein the solvent isethyl acetate or methanol.
 40. The method of claim 30, wherein theconjugate addition is carried out by treating the elimination product offormula (VII) or (VIII) with a second organo-Grignard reagent or with asecond an organo-lithium reagent in the presence of a dialkylzinc orzinc chloride or a copper (I) salt or a trialkylaluminium in a solventat a temperature from −100° C. to 0° C. to produce a compound of formula(II).
 41. The method of claim 40, wherein the solvent is selected fromtetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether andt-butyl methyl ether.
 42. The method of claim 30, wherein the leavinggroup X in the compound of formula (III) or (IV) is acetoxy.
 43. Themethod of claim 30, wherein the leaving group X in the compound offormula (III) or (IV) is halogen or sulfonic acid ester group.
 44. Anenantiomerically pure compound made by the method of claim
 30. 45. Thecompound of claim 44, whose enantiomeric purity is 98% or above.
 46. Amethod of producing a compound of one of the formulae shown below:

in which the substituents R and R′ and the wedges have the meaningsindicated in claim 30, which comprises providing a compound of formula(I) or (II) produced by the method of claim 30, converting said compoundto a compound of formula (XI), (XII), (XIII) or (XIV), and optionallyfurther converting said compound into a pharmaceutically acceptablesalt.
 47. The method of claim 46, wherein said conversion is via anintermediate (XV)-(XVIII) shown below:

in which the substituents R and R′ and the wedges have the meaningsindicated above.
 48. The method of claim 47, wherein the intermediate offormula (XV)-(XVIII) is converted to a compound of formula (I) or (II)by transforming the phenyl ring to a carboxylic acid and then to anamine.
 49. The method of claim 47, wherein the intermediate of formula(XV)-(XVIII) is converted to a compound of formula (I) or (II) bytransforming the carboxylic acid group into an amine and oxidizing thephenyl group to an acid.
 50. The method of claim 47, wherein theintermediate of formula (XV)-(XVIII) is converted to a compound offormula (I) or (II) by protecting the carboxylic acid group, oxidizingthe phenyl ring to a second carboxylic acid group, protecting the secondcarboxylic acid group, selectively de-protecting the first carboxylicacid group, transforming the first carboxylic acid group to an amine,and de-protecting the second carboxylic acid group.
 51. A method ofproducing a compound of the formula (XV)-(XVIII) shown below:

in which the substituents R and R′ and the wedges have the meaningsindicated in claim 30, which comprises providing a compound of formula(I) or (II) produced by the method of claim 30, and converting saidcompound to a compound of formula (XV)-(XVIII).
 52. An enantiomericallypure compound of the formula:

wherein R and R′ represent C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₃-C₁₀cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, thesubstituents being trans, and at least one of R and R′ not being methyl.53. Any of the following compounds (3S,4S)-3,4-diethyl-cyclopentanone;(3R,4R)-3,4-diethyl-cyclopentanone;(3S,4S)-3-ethyl-4-methyl-cyclopentanone;(3R,4R)-3-ethyl-4-methyl-cyclopentanone;(3S,4S)-3-methyl-4-propyl-cyclopentanone;(3R,4R)-3-methyl-4-propyl-cyclopentanone;(3S,4S)-3-ethyl-4-propyl-cyclopentanone;(3R,4R)-3-ethyl-4-propyl-cyclopentanone.